10b-Substituted hexahydropyrrolo-isoquinolines: studies on diastereoselective formation of a quaternary carbon stereocenter via N-acyliminium ion cyclization

The stereoselective synthesis of hexahydro-pyrroloisoquinolines with a quaternary carbon stereocenter is described. The presented methodology employs the addition of a Grignard reagent to the carbonyl group of imide , derived from l-tartaric acid, followed by acetylation and BF3·Et2O induced cyclization. The acetylation–cyclization sequence can be run either as a one-pot process, or stepwise in a selected solvents. The crucial step, an acid-catalyzed carbon–carbon bond-forming reaction via an N-acyliminium ion offers high stereoselectivity, which has been shown to be strongly dependent on the size of the R1 substituents and the reaction conditions, that is, choice of solvent, amount of a Lewis acid, temperature, and concentration of the substrate. Based on the results observed, participation of solvent in the cyclization, via an N-acyliminium cation is proposed.